Indolopteridines and process for preparing same



Patented June 12 1951 UNITED STATES INDOLOPTERIDINES AND PROCESS FOR I PREPARING SAME Norman Robert Campbell,

Maurice Edward Hugh Fitzgerald, Henry Oswald Jackson Collier, and.- James Henry Dunsmuir, London, England, as signers to Allen & Hanburys Limited, London, England, a British company No Drawing. Application June 6, 1950, Serial No, 166,529. In Great Britain June 24, 1949- 12 Claims. (01.

This invention relates to anti-bacterial substances.

eral formula:

N N N l t NH: I

where R is hydrogen or a methyl, ethyl or propyl group.

It has now been discovered, according to this invention, that compounds of the general Formula I can be produced by condensation of 5-nitroso-2.4.fi-triaminopyrimidine with an O- cyl-indoxyl or an O-acyl-N-alkyl-indoxyl where the alkyl group is a methyl, ethyl or propyl group.

Thus, according to the process of the present invention for the manufacture of pteridines of the general Formula I, 5-nitroso-2.4.6-triamino-" pyrimidine is condensed with an O-acyl-indoxyl or an O-acyl-N-alkyl-indoxyl where the alkyl group is a methyl, ethyl or propyl group, in solution or suspension in a solvent in the presence of a condensing agent. 3,

A mixture of solvents maybe used if desired.

The reaction can be formulated as follows: 7

. completion'of the reaction the solvent may be wholly or partly removed by distillation, if necessary, and the residue extracted with hot water. The solid product'is extracted with small quantities of a solvent such as alcohol, methanol or acetone and further purified by recrystallisation or by chromatography.

The following examples illustrate how the process of the invention may be carried into efiect:

1. 154 gms. of 5-nitroso-triaminopyrimidine are suspended-in 25, litres of boiling water and boiled under reflux in an atmosphere of nitrogen for thirty minutes. ml. of piperidine are then added and an-alcoholic solution of 189 gms. of O-acetyl-N-methyl-indoxyl added slowly with vigorous fstirring. The mixture is boiled under reflux, with continued stirring, still in an atmosphere of nitrogen, for a further five to ten minutesfthen filtered hot and the separated solid boiled once with water, then once or twice with alcohol, until free from extraneousblue colour. The orange-coloured product may be recrystallised from dimethyl-formamide or pyridine, or from alcohol in an extraction apparatus. It then melts with decomposition between 370 and 380 C.

2. A mixture of'4.6 gms. of S-nitrosotriaminopyrimidine with 800 ml. of water was boiled under reflux for twenty minutes in aislow stream of nitrogen. 4 ml." of piperidine were added, followed by a solution of 5.6 gms. of O-acetyl-N- ethyl-indoxyl in 100 ml. 01; ethyl alcohol. The mixture was then boiled under reflux, in an atmosphere of nitrogen, for ten minutes and filtered. The crude solid product was washed with hot water and with alcohol then extracted with hot alcohol and recrystallised from pyridine. The orange-yellow product, 2.4-diamino-l'-ethylindo1o-(2".3"-6.7)pteridine, melted at 356-357" C.

3. A mixture of 2.5 gms. of 5-nitrosotriaminopyrimidine with 450 m1. of water was boiled under reflux for twenty minutes in a slow stream of nitrogen. 4 ml. of piperidine were added, followed by a solution of 3 gms. of O-acetyl-N-npropyl-indoxyl in ml. of alcohol. The mixture was then boiled under reflux, in an atmosphere of nitrogen, for fifteen minutes, cooled and filtered. The crude solid product was washed with water and with alcohol and recrystallised from alcohol. The yellow product, ZA-diamino- 1-n-propylindolo(2'.3-6.7)pteridine, melted at 328329 C.

4. A mixture of 4.6 gms. of 5-nitrosotriaminopyrimidine with 800 ml. of water was boiled under reflux for twenty minutes in a slow stream of nitrogen. 10 ml. of a ten per cent solution of dimethylamine in alcohol were added followed by a solution of 5.6 gms. of O-acetyl-N-methylindoxyl in 50 ml. of alcohol. The mixture was then boiled under reflux for four minutes and filtered. The crudeesolid product was washed with hot water and with alcohol, extracted thoroughly with boiling alcohol and recrystallised from pyridine. The orange-yellow product, 2.4- diamino 1' methylindolo-(2".3" 6.7')-pteridine, melted at 373-374" C.

5. A mixture of 4.6 gms.--of 5-nitrosotriaminopyrimidine with 800 m1. of --water was boiled under reflux for twenty minutes inazslowstream of nitrogen. 4 ml. of piperid ine were added, followed by a solution of 5.2 gms. of O-acetylindoxyl in 100 ml. of water. The mixture was then boiled under reflux for fifteen minutes and filtered. The crude solid product was washed with hot water and with hot alcohol and recrystallised from pyridine. The orange-yellow product, '2.4-diam'ino -indo-lo 4C2 .3" -6'.7 )pteridine, melted above .3710 C.

The pteridines of the present invention are inhibitory to the .growth .of Vibrio cholerae in a peptone water 'medium in high dilution.

All the above-mentioned compounds were tested against Vibrio cholerae in'peptone water and the values :shown in the following table were obtained for the minimum inhibitory concentration in g. per ml. after 24 hours against organisms per ml. In the table, R is the substituent in the formula .givenzalbove.

What we claim is: 1. New pteridines of the general formula:

where R is selected from the group consisting of hydrogen and alkyl groups containing less thanfour carbonatoms.

2. 2.4-diamino-1-ethylindo1o (2'.3-6.7) pteridine.

3. 2.4-diamino-1 n- -propylindo1o-'(2'.3'-6.7) pteridine.

4. 2.4 diamino 1' -methy1indolo--.(2'.3'-6.'7) :pteridine.

'5. 2.4-diamino indolo- (2 (.3 -6.'7) pteridine.

4 6. A process for the manufacture of pteridines of the general formula:

where R. is selectedfrom the group consisting of hydrogen and alkyl groups containing less than four carbon atoms, which comprises condensing 5-nitroso-2.4.6-triaminopyrimidine with an in- .doxyl derivative selected from the group consistcondensing agent of the acid binding type.

9. A process for the manufacture of 2.4-diamino-1 n propylindolo (2.3-6.7)pteridine which comprises condensing 5-nitroso-2.4.6-triaminopyrimidine with O-acetyl-N-n-propyl-indoxyl in the presence of ethyl alcohol and of piperidine as a condensing agent of the acid binding type.

10. A process for the manufacture of 2.4-diamino-1 methylindolo 62".3 fimpte'rldine which comprises condensing 5-nitroso-2;4.'6-'triaminopyrimidine with O acetyl N-methyl-indoxyl in the presence of ethyl alcohol and of piperidine as a condensing agent of the acid binding type.

11. A process for the manufacture of 2.4-diamino 1 methylindolo (2.3' 6.7)pteridine which comprises condensing 5nitroso-2.4.6-tri aminopyrimidine with O-acetyl N methyl indoxyl in the presence of ethyl alcohol and of dimethylamine as a condensing agent of the acid binding type.

12. A process for the manufacture of 2.4-diamino 'indolo 2.3'-6.7) pteri'dine which comprises condensing 5-nitroso-2. lfi-triaminopyrimidine with O-acetyl-indoxyl in the presence of ethyl alcohol and of piperidine as a condensing agent of the acid binding type.

NORMAN ROBERT CAIWPBELL. MAURICE EDWARD HUGH FITZGERALD. HENRY OSWALD JACKSON COLLIER. JAMES HENRY DUNSMUIR.

REFERENCES CITED The following references are of record in the file of this patent:

Hackh Chemical Dictionary, 219-220,

third edition (1944) 

1. NEW PTERIDINES OF THE GENERAL FORMULA:
 6. A PROCESS FOR THE MANUFACTURE OF PTERIDINES OF THE GENERAL FORMULA: 